title: Differential responses to JNJ-37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague-Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics.
abstract: JNJ-37822681 is a potent, specific and fast dissociating dopamine D2 receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague-Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ-37822681 in terms of extrapyramidal (EPS)-like clinical signs and prolactin-mediated tissue changes in the mammary gland. Monkeys showed severe EPS-like clinical signs such as abnormal posture, abnormal eye movements and hallucination-like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ-37822681-induced EPS-like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin-related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ-37822681. The monkey toxicology studies did not provide an exposure-based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ-37822681-associated adverse events in humans than the Sprague-Dawley rat.
authors.affiliation: Janssen Research and Development, a division of Janssen Pharmaceutica NV, Drug Safety Sciences, Department of Preclinical Project Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: de Waal
authors.forename: Maria
authors.initials: M
authors.lastname: Desmidt
authors.forename: Sven
authors.initials: S
authors.lastname: Korte
authors.forename: Marc
authors.initials: M
authors.lastname: Niehoff
authors.forename: Kevan
authors.initials: K
authors.lastname: Chase
authors.forename: Wayne
authors.initials: W
authors.lastname: Arrowsmith
authors.forename: Ann
authors.initials: A
authors.lastname: Lampo
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D065127:Dopamine D2 Receptor Antagonists / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology*; D010880:Piperidines / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D011388:Prolactin / Q000378:metabolism*; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy; D018675:Toxicity Tests
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; C576398:N-(1-(3,4-difluorobenzyl)piperidin-4-yl)-6-(trifluoromethyl)pyridazin-3-amine; D010880:Piperidines; D011724:Pyridazines; D011388:Prolactin
keywords: EPS; JNJ-37822681; antipsychotic; dopamine D2 receptor antagonist; extrapyramidal symptoms; monkey; prolactin; rat